(Applicant's Abstract) The guiding hypothesis of this SCOR renewal is that allergic asthma results from a dysregulated immune response to allergens. The dysregulated immune response sets in motion a cascade resulting in the accumulation of IgE-sensitized mast cells and allergen-specific Th2 cells in airway mucosa, airway hyperreactivity, eosinophilic inflammation and airway remodeling with mucous cell metaplasia. The proposal consists of four projects, each with a clinical component, and three supporting cores, including a clinical core. Dr. Lipscomb's project proposes to study the role of lung antigen presenting cells, particularly lung dendritic cells (DCs), in pulmonary immune responses to allergens. Lipscomb will adoptively transfer T cell clones and lung DCs in a murine allergic pulmonary inflammation model and use human monocyte-derived DCs, human bronchoalveolar lavage fluids and bronchial biopsies in these studies. Dr. Oliver's project will exploit her laboratory's observation showing that basophils that don't release histamine following high affinity IgE receptor (FceRI) crossing-linking are deficient in the tyrosine kinase, Syk. Oliver proposes to determine whether people with such "non-releaser" basophils are protected from asthma. She will also explore the mechanisms for loss of Syk activity in non-releaser basophils and assess whether decreased serum IgE induced by anti-IgE therapy leads to a decrease in FceRI expression on human lung mast cells. Dr. Sklar's project will examine the molecular mechanisms involved in the preferential recruitment of eosinophils and basophils into the bronchial mucosa in asthma. Sklar will use novel technology to quantify changes in affinity and avidity of the molecules involved in the cell-cell interactions that model leukocyte adhesion to the endothelium. Dr. Tesfaigzi's project proposes to study the role of mediators generated in asthmatic lungs in causing mucous cell metaplasia. Specifically, Tesfaigzi win seek a role for suppression of normal apoptosis by the pro-apoptotic regulator, Bax, in mucous cell metaplasia. He will use an innovative mouse bronchiolar explant model, cytokine receptor and Bax knockout mice, human bronchial brushings, and autopsy tissues from asthmatics and controls. Collectively, the four projects will identify mechanisms involved in critical pathways that lead to asthmatic lung inflammation and bronchial remodeling with the goal of identifying possible targets for prevention or treatment of asthma.